: The clinically available forms of human interferon (IFN) alpha-IFNalpha2alpha (Roferon-A), IFNalpha2b (Intron). Consensus IFN and pegylated IFNs (PEG Intron and Pegasys) - are useful in the treatment of several viral diseases and cancers. However, when used at therapeutic doses they produce frequent and sometimes serious side effects, including fever, myalgia, CNS effects and leukopenia, which limit their use. IFNinterferon, a structurally related interferon in ruminants, has similar antiviral and antitumor properties as the IFNalpha's but little or no toxicity. However, as a xenoprotein IFNinterferon is not a suitable candidate for development as a parenteral drug for humans. We have synthesized an analog of human IFNalpha2b, NLVgalpha2b, which contains five amino acid substitutions at positions19, 20, 22, 24 and 27 using residues from the corresponding positions in the IFNinterferon molecule. The in vitro and in vivo data from our SBIR phase I study demonstrated that these substitutions conferred markedly reduced cellular toxicity on the resulting molecule without diminishing its antiviral and antitumor activities. In this phase II project we will advance NLVgalpha2b into preclinical development by optimizing expression of this recombinant IFN in yeast, producing pegylated as well as unpegylated preparations and subjecting them to rigorous evaluation in well established animal models. The antiviral, anticancer, immunogenicity and toxicity profiles of NLVgalpha2b will be compared with those of commercially available IFNalpha2b. If this project is successful, it should be possible to administer NLVgalpha2b to patients in higher doses than can be achieved with current IFNalpha's, resulting in improved clinical outcomes.